Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions

ABSTRACT

The present invention relates to the CGRP antagonists of general formula  
                 
 
wherein A, X and R 1  to R 3  are defined as in claim  1,  the tautomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.

The present invention relates to the CGRP antagonists of general formula

the tautomers, the diastereomers, the enantiomers, the hydrates thereof,the mixtures thereof and the salts thereof as well as the hydrates ofthe salts, particularly the physiologically acceptable salts thereofwith inorganic or organic acids or bases, pharmaceutical compositionscontaining these compounds, the use thereof and processes for thepreparation thereof.

In the above general formula (I)

-   -   A denotes a group of formula    -   X denotes an oxygen atom, a methylene or NH group,    -   R¹ denotes a group of formula    -   —NR²R³ denotes a group of formula

Particularly preferred compounds of the above general formula (I) arethe following, for example: 1

151

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2179

2306

2180

2307

2181

2308

2182

2309

2183

2310

2184

2311

2185

2312

2186

2313

2187

2314

2188

2315

2189

2316

2190

2317

2191

2318

2192

2319

2193

2320

2194

2321

2195

2322

2196

2323

2197

2324

2198

2325

2199

2326

2200

2327

2201

2328

2202

2329

2203

2330

2204

2331

2205

2332

2206

2333

2207

2334

2208

2335

2209

2336

2210

2337

2211

2338

2212

2339

2213

2340

2214

2341

2215

2342

2216

2343

2217

2344

2218

2345

2219

2346

2220

2347

2221

2348

2222

2349

2223

2350

2224

2351

2225

2352

2226

2353

2227

the tautomers, the diastereomers, the enantiomers, the hydrates thereof,the mixtures thereof and the salts thereof as well as the hydrates ofthe salts.

The compounds of general formula (I) are prepared by methods known inprinciple. The following methods have proved particularly useful forpreparing the compounds of general formula (I) according to theinvention:

(a) In order to prepare compounds of general formula

-   -   wherein X denotes the oxygen atom or the NH group and A and R¹        to R³ are as hereinbefore defined:    -   reacting a piperidine of general formula    -   wherein R¹ is as hereinbefore defined,    -   (i) with a carbonic acid derivative of general formula    -   wherein G denotes a nucleofugic group which may be identical or        different, preferably the phenoxy, 1H-imidazol-1-yl,        1H-1,2,4-triazol-1-yl, trichloromethoxy or        2,5-dioxopyrrolidin-1-yloxy group, with the proviso that X        denotes the NH group, or    -   (ii) with a carbonic acid derivative of general formula    -   wherein G denotes a nucleofugic group which may be identical or        different, preferably the chlorine atom, the p-nitrophenoxy or        trichloromethoxy group, with the proviso that X denotes the        oxygen atom,    -   and with a compound of general formula    -   wherein X denotes the oxygen atom or an—NH group and A, R² and        R³ are as hereinbefore defined, with the proviso that R² and R³        do not contain any other free primary or secondary aliphatic        amino function.

Any primary or secondary amino function which may be present in thegroup —NR²R³ is in each case provided with a suitable protective group.

The reactions which are theoretically two-step reactions are usuallycarried out as one-pot processes, preferably by reacting one of the twocomponents (Ill) or (V) with equimolar quantities of the carbonic acidderivative of general formula (IV) in a suitable solvent at lowertemperature in the first stage, then adding at least equimolar amountsof the other component (Ill) or (V) and finishing the reaction atelevated temperature. The reactions with bis-(trichloromethyl)-carbonateare preferably carried out in the presence of at least 2 equivalents(based on bis-(trichloromethyl)-carbonate) of a tertiary base, e.g.triethylamine, N-ethyl-diisopropylamine, pyridine,1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane or1,8-diazabicyclo[5,4,0]undec-7-ene. Examples of solvents, which shouldbe anhydrous, include tetrahydrofuran, dioxane, dimethyl formamide,dimethylacetamide, N-methyl-2-pyrrolidone,1,3-dimethyl-2-imidazolidinone or acetonitrile; ifbis-(trichloromethyl)-carbonate is used as the carbonyl componentanhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethaneor trichloroethylene are preferred. The reaction temperatures for thefirst reaction step are between −30 and +25° C., preferably −5 and +10°C., for the second reaction step they are between +15° C. and theboiling temperature of the solvent used, preferably between +20° C. and+70° C. (cf. also: H. A. Staab and W. Rohr, “Synthesen mitheterocyclischen Amiden (Azoliden)”, Neuere Methoden der PräparativenOrganischen Chemie, Vol. V, p. 53-93, Verlag Chemie, Weinheim/Bergstr.,1967; P. Majer and R. S. Randad, J. Org. Chem. 59, 1937-1938 (1994); K.Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, TetrahedronLetters 24 (42), 4569-4572 (1983); S. R. Sandier and W. Karo in “OrganicFunctional Group Preparations”, Vol. II, p. 223-245, Academis Press, NewYork 1971).

(b) In order to prepare compounds of general formula

-   -   wherein X denotes the methylene group and A and R¹ to R³ are as        hereinbefore defined, with the proviso that no other free        primary or secondary aliphatic amino functions are present in        the molecule:    -   coupling a carboxylic acid of general formula    -   wherein A, R² and R³ are as hereinbefore defined, with a        piperidine of general formula    -   wherein R¹ is as hereinbefore defined.

The coupling is preferably carried out using methods known from peptidechemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol.15/2), for example using carbodiimides such as e.g.dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) orethyl-(3-dimethylaminopropyl)-carbodiimide,O-(1H-benzotriazol-1-yl)-N,N—N′, N′-tetramethyluroniumhexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reactionspeed can be increased. The couplings are normally carried out withequimolar amounts of the coupling components as well as the couplingreagent in solvents such as dichloromethane, tetrahydrofuran,acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA),N-methylpyrrolidone (NMP) or mixtures thereof and at temperaturesbetween −30 and +30° C., preferably −20 and, +25° C. If necessary,N-ethyl-diisopropylamine (Hünig base) is preferably used as anadditional auxiliary base.

The so-called anhydride process is used as a further coupling method forsynthesising compounds of general formula (I) (cf. also: M. Bodanszky,“Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky,“Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). TheVaughan variant of the mixed anhydride process is preferred (J. R.Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixedanhydride of the carboxylic acid of general formula (VI) which is to becoupled and monoisobutyl carbonate is obtained, using isobutylchlorocarbonate in the presence of bases such as 4-methylmorpholine or4-ethylmorpholine. The preparation of this mixed anhydride and thecoupling with amines are carried out in a one-pot process, using theabove-mentioned solvents and at temperatures between −20 and +25° C.,preferably 0° C. and +25° C.

(c) In order to prepare compounds of general formula

-   -   wherein X denotes the methylene group and A and R² and R³ are as        hereinbefore defined, with the proviso that these groups do not        contain any free primary or secondary amine:    -   coupling a compound of general formula    -   wherein A, R² and R³ are as hereinbefore defined, with the        proviso that R² and R³ do not contain any free primary or        secondary amine, and Nu denotes a leaving group, for example a        halogen atom, such as the chlorine, bromine or iodine atom, an        alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl        moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group        optionally mono-, di- or trisubstituted by chlorine or bromine        atoms or by methyl or nitro groups, while the substituents may        be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl        optionally substituted by one or two methyl groups in the carbon        skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl,        1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl p-nitrophenyl,        2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl,        pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy,        2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy,        phthalimidyloxy, 1H-benzo-triazol-1-yloxy or azide group,    -   with a piperidine of general formula    -   wherein R¹ is as hereinbefore defined.

The reaction is carried out under Schotten-Baumann or Einhom conditions,i.e. the components are reacted in the presence of at least oneequivalent of an auxiliary base at temperatures between −50° C. and+120° C., preferably −10° C. and +30° C., and optionally in the presenceof solvents. The auxiliary bases used are preferably alkali metal andalkaline earth metal hydroxides, e.g. sodium hydroxide, potassiumhydroxide or barium hydroxide, alkali metal carbonates, e.g. sodiumcarbonate, potassium carbonate or caesium carbonate, alkali metalacetates, e.g. sodium or potassium acetate, as well as tertiary amines,e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine,N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, thesolvents used may be, for example, dichloromethane, tetrahydrofuran,1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide,N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkalineearth metal hydroxides, alkali metal carbonates or acetates are used asthe auxiliary bases, water may also be added to the reaction mixture ascosolvent.

(d) In order to prepare compounds of general formula

-   -   wherein A, X and R¹ to R³ are as hereinbefore defined:    -   coupling a carboxylic acid of general formula    -   wherein A, X and R¹ are as hereinbefore defined, with an amine        of general formula HNR²R³, wherein R² and R³ are as hereinbefore        defined, with the proviso that they do not contain any other        free primary or secondary aliphatic amino function.

The coupling is preferably carried out using methods known from peptidechemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol.15/2), for example using carbodiimides such as e.g.dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) orethyl-(3-dimethylaminopropyl)-carbodiimide,O-(1H-benzotriazol-1-yl)-N,N—N′, N′-tetramethyluroniumhexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reactionspeed can be increased. The couplings are normally carried out withequimolar amounts of the coupling components as well as the couplingreagent in solvents such as dichloromethane, tetrahydrofuran,acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA),N-methylpyrrolidone (NMP) or mixtures thereof and at temperaturesbetween −30 and +30° C., preferably −20 and +25° C. If necessary,N-ethyl-diisopropylamine (Hünig base) is preferably used as anadditional auxiliary base.

The so-called anhydride process is used as a further coupling method forsynthesising compounds of general formula (I) (cf. also: M. Bodanszky,“Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky,“Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). TheVaughan variant of the mixed anhydride process is preferred (J. R.Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixedanhydride is obtained from the carboxylic acid of general formula (VIII)which is to be coupled and monoisobutyl carbonate, using isobutylchlorocarbonate in the presence of bases such as 4-methylmorpholine or4-ethylmorpholine. The preparation of this mixed anhydride and thecoupling with the amines of general formula HNR²R³ are carried out in aone-pot process, using the above-mentioned solvents and at temperaturesbetween −20 and +25° C., preferably 0° C. and +25° C.

(e) In order to prepare compounds of general formula

-   -   wherein A, X and R¹ to R³ are as hereinbefore defined, with the        proviso that no free primary or secondary amine is present in        the molecule:    -   coupling a compound of general formula    -   wherein A, X and R¹ are as hereinbefore defined and Nu denotes a        leaving group, for example a halogen atom, such as the chlorine,        bromine or iodine atom, an alkyl-sulphonyloxy group with 1 to 10        carbon atoms in the alkyl moiety, a phenylsulphonyloxy or        naphthylsulphonyloxy group optionally mono-, di- or        trisubstituted by chlorine or bromine atoms or by methyl or        nitro groups, while the substituents may be identical or        different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally        substituted by one or two methyl groups in the carbon skeleton,        a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl,        1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl,        2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl,        pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy,        2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy,        phthalimidyloxy, 1H-benzo-triazol-1-yloxy or azide group,    -   with an amine of general formula HNR²R³, wherein R² and R³ are        as hereinbefore defined, with the proviso that no free        carboxylic acid and/or no other free primary or secondary        aliphatic amino function is present.

The reaction is carried out under Schotten-Baumann or Einhom conditions,i.e. the components are reacted in the presence of at least oneequivalent of an auxiliary base at temperatures between −50° C. and+120° C., preferably −10° C. and +30° C., and optionally in the presenceof solvents. The auxiliary bases used are preferably alkali metal andalkaline earth metal hydroxides, e.g. sodium hydroxide, potassiumhydroxide or barium hydroxide, alkali metal carbonates, e.g. sodiumcarbonate, potassium carbonate or caesium carbonate, alkali metalacetates, e.g. sodium or potassium acetate, as well as tertiary amines,e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine,N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, thesolvents used may be, for example, dichloromethane, tetrahydrofuran,1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide,N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkalineearth metal hydroxides, alkali metal carbonates or acetates are used asthe auxiliary bases, water may also be added to the reaction mixture ascosolvent.

The new compounds of general formula (I) according to the inventioncontain one or more chiral centres. If for example there are two chiralcentres the compounds may occur in the form of two pairs ofdiastereomeric antipodes. The invention covers the individual isomers aswell as the mixtures thereof.

The diastereomers may be separated on the basis of their differentphysico-chemical properties, e.g. by fractional crystallisation fromsuitable solvents, by high pressure liquid or column chromatography,using chiral or preferably non-chiral stationary phases.

Racemates covered by general formula (I) may be separated for example byHPLC on suitable chiral stationary phases (e.g. Chiral AGP, ChiralpakAD). Racemates which contain a basic function can also be separated viathe diastereomeric, optically active salts which are produced onreacting with an optically active acid, for example (+) or (−)-tartaricacid, (+) or (−)-diacetyl tartaric acid, (+) or (−)-monomethyl tartrateor (+)-camphorsulphonic acid.

According to a conventional method of separating isomers, the racemateof a compound of general formula (I) is reacted with one of theabove-mentioned optically active acids or bases in equimolar amounts ina solvent and the resulting crystalline, diastereomeric, opticallyactive salts thereof are separated using their different solubilities.This reaction may be carried out in any type of solvent provided that itis sufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof, for example in aratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralised with a base such assodium carbonate or potassium carbonate, or with a suitable acid, e.g.dilute hydrochloric acid or aqueous methanesulphonic acid, and in thisway the corresponding free compound is obtained in the (+) or (−) form.

The (R) or (S) enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formula I may also beobtained by performing the syntheses described above with a suitablereaction component in the (R) or (S) configuration.

The starting compounds of general formula (Ill), if they are not knownfrom the literature or commercially available, are obtained using theprocesses described in International Patent Application WO 98/11128 andDE 199 52 146. The starting compounds of general formula (IV) arecommercially available. Compounds of general formula (V) may be obtainedby methods familiar to the peptide chemist from protected phenylalaninesand amines of general formula HNR²R³.

The phenyalanine derivatives needed to prepare the optically purecompounds of general formula (V) may be prepared from the compounds ofgeneral formula

-   -   wherein A is as hereinbefore defined and R denotes an unbranched        alkyl group, preferably the methyl or ethyl group, by racemate        cleaving.

This racemate cleaving may be carried out using enzymatic methods, whileonly one enantiomer of the racemate is transformed and the resultingmixture is then separated using physicochemical methods, preferablyusing chromatographic methods. A suitable enzyme system for this step isthe enzyme alkalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd). Thecompounds of general formula (X) can then be converted into theenantiomerically pure compounds of general formula (V) using methodsfamiliar to the peptide chemist.

If the group X in compounds of general formula (V) denotes the oxygenatom, the hydroxycarboxylic acids of general formula

-   -   wherein A is as hereinbefore defined which are needed for the        synthesis may be obtained from compounds of general formula (X),        with the proviso that R denotes the hydrogen atom.

With the proviso that the group A does not contain an amino ormethylamino group, by diazotising compounds of general formula (X) witha suitable diazotising reagent, preferably sodium nitrite in an acidmedium, it is possible to obtain the compounds of general formula (XI).If enantiomerically pure compounds are used the correspondingenantiomerically pure hydroxycarboxylic acid compounds are obtained, theconfiguration being retained as the reaction proceeds.

Another method of obtaining compounds of general formula (XI) whereinthe groups A are as hereinbefore defined comprises alkylating thecompound

-   -   with correspondingly substituted benzylchlorides, benzylbromides        or benzyliodides of general formula    -   wherein A is as hereinbefore defined and X denotes a chlorine,        bromine or iodine atom, analogously to methods known from the        literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D.        Katz, Org. Lett. 2, 2165-2167 [2000]).

The diastereomeric products formed may then be separated usingphysicochemical methods, preferably chromatographic methods. Thehydrolytic cleaving of the chiral auxiliary, coupling with amines ofgeneral formula HNR²R³ and cleaving of the benzyl protective group alsoprovides a way of obtaining enantiomerically pure hydroxycarboxylic acidcompounds of general formula (V).

Compounds of general formula (XI) wherein the groups A are ashereinbefore defined may also be obtained by boiling down2-acetylamino-3-phenyl-acrylic acids of general formula

-   -   using strong acids and subsequently reducing the        2-hydroxy-3-phenyl-acrylic acids formed.

The starting compounds of general formula (VI) are obtained for exampleby reacting amines of general formula HNR²R³ with2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids and subsequentlyhydrolytically cleaving the alkyl group. The2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids needed may be preparedanalogously to methods known from the literature (David A. Evans,Leester D. Wu, John J. M. Wiener, Jeffrey S. Johnson, David H. B. Ripinand Jason S. Tedrow, J. Org. Chem 64, 6411-6417 [1999]; Saul G. Cohenand Aleksander Milovanovic, J. Am. Chem. Soc. 90, 3495-3502 [1968];Hiroyuki Kawano, Youichi Ishii, Takao Ikariya, Masahiko Saburi, SadaoYoshikawa, Yasuzo Uchida and Hidenori Kumobayashi, Tetrahedron Letters28, 1905-1908 [1987]). Carboxylic acids of general formula (VIII) may beprepared by the methods recited in WO 98/11128 from generally availablestarting materials.

The compounds of general formula I obtained may, if they containsuitable basic functions, be converted, particularly for pharmaceuticaluse, into their physiologically acceptable salts with inorganic ororganic acids. Suitable acids include for example hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid,methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid,p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid,lactic acid, mandelic acid, malic acid, citric acid, tartaric acid ormaleic acid.

The present invention relates to racemates if the compounds of generalformula (I) have only one chiral element. However, the application alsoincludes the individual diastereomeric pairs of antipodes or mixturesthereof which are obtained if there is more than one chiral element inthe compounds of general formula (I), as well as the individualoptically active enantiomers of which the above-mentioned racemates aremade up.

Also included in the subject matter of this invention are the compoundsaccording to the invention, including the salts thereof, in which one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

The new compounds of general formula (I) and the physiologicallyacceptable salts thereof have valuable pharmacological properties, basedon their selective CGRP-antagonistic properties. The invention furtherrelates to pharmaceutical compositions containing these compounds, theiruse and the preparation thereof.

The new compounds mentioned above and the physiologically acceptablesalts thereof have CGRP-antagonistic properties and exhibit goodaffinities in CGRP receptor binding studies. The compounds displayCGRP-antagonistic properties in the pharmacological test systemsdescribed hereinafter.

The following experiments were carried out to demonstrate the affinityof the above-mentioned compounds for human CGRP-receptors and theirantagonistic properties:

A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRPReceptor)

SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. Themedium is removed from confluent cultures. The cells are washed twicewith PBS buffer (Gibco 041-04190 M), detached by the addition of PBSbuffer mixed with 0.02% EDTA, and isolated by centrifuging. Afterresuspension in 20 ml of “Balanced Salts Solution” [BSS (in mM): NaCl120, KCl 5.4, NaHCO₃ 16.2, MgSO₄ 0.8, NaHPO₄ 1.0, CaCl₂ 1.8, D-glucose5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100×g andresuspended in BSS. After the number of cells has been determined, thecells are homogenised using an Ultra-Turrax and centrifuged for 10minutes at 3000×g. The supernatant is discarded and the pellet isrecentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl₂, 1 mMEDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1%bacitracin, and resuspended (1 ml/1000000 cells). The homogenisedproduct is frozen at −80° C. The membrane preparations are stable formore than 6 weeks under these conditions.

After thawing, the homogenised product is diluted 1:10 with assay buffer(50 mM Tris, 150 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, pH 7.40) andhomogenised for 30 seconds with an Ultra-Turrax. 230 μl of thehomogenised product are incubated for 180 minutes at ambient temperaturewith 50 pM ¹²⁵I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham)and increasing concentrations of the test substances in a total volumeof 250 μl. The incubation is ended by rapid filtration throughGF/B-glass fibre filters treated with polyethyleneimine (0.1%) using acell harvester. The protein-bound radioactivity is measured using agamma counter. Non-specific binding is defined as the boundradioactivity in the presence of 1 μM human CGRP-alpha duringincubation.

The concentration binding curves are analysed using computer-aidednon-linear curve matching.

The compounds mentioned hereinbefore show IC₅₀ values ≦10000 nM in thetest described.

B. CGRP Antagonism in SK-N-MC Cells

SK-N-MC cells (1 million cells) are washed twice with 250 μl incubationbuffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4)and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP(10 μl) as agonist in increasing concentrations (10⁻¹¹ to 10⁻⁶ M), oradditionally the substance in 3 to 4 different concentrations, themixture is incubated for another 15 minutes.

Intracellular cAMP is then extracted by the addition of 20 μl of 1M HCland centrifugation (2000×g, 4° C., for 15 minutes). The supernatants arefrozen in liquid nitrogen and stored at −20° C.

The cAMP contents of the samples are determined by radioimmunoassay(Messrs. Amersham) and the pA₂ values of antagonistically actingsubstances are determined graphically.

The compounds of general formula I exhibit CGRP-antagonistic propertiesin the in vitro test model described, in a dosage range between 10⁻¹²and 10⁻⁵ M.

In view of their pharmacological properties the compounds of generalformula I and the salts thereof with physiologically acceptable acidsare thus suitable for the acute and prophylactic treatment of headaches,particularly migraine or cluster headaches. Moreover, the compounds ofgeneral formula I also have a positive effect on the following diseases:non-insulin-dependent diabetes mellitus (“NIDDM”), complex regional painsyndrome (CRPS1), cardiovascular diseases, morphine tolerance, diarrhoeacaused by clostridium toxin, skin diseases, particularly thermal andradiation-induced skin damage including sunburn, inflammatory diseases,e.g. inflammatory diseases of the joints (arthritis), neurogenicinflammation of the oral mucosa, inflammatory lung diseases, allergicrhinitis, asthma, diseases accompanied by excessive vasodilatation andresultant reduced blood supply to the tissues, e.g. shock and sepsis. Inaddition, the compounds according to the invention have a generalpain-relieving effect.

The symptoms of menopausal hot flushes caused by vasodilatation andincreased blood flow in oestrogen-deficient women and hormone-treatedpatients with prostate carcinoma are favourably affected by theCGRP-antagonists of the present application in a preventive andacute-therapeutic capacity, this therapeutic approach beingdistinguished from hormone replacement by the absence of side effects.

The dosage required to achieve a corresponding effect is conveniently0.01 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of bodyweight, when administered intravenously or subcutaneously and 0.01 to 20mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight whenadministered orally, and 0.01 to 10 mg/kg of body weight, preferably 0.1to 10 mg/kg of body weight when administered nasally or by inhalation, 1to 3×a day in each case.

If the treatment with CGRP antagonists and/or CGRP release inhibitors isgiven as a supplement to conventional hormone replacement, it isadvisable to reduce the doses specified above, in which case the dosagemay be from ⅕ of the lower limits mentioned above up to 1/1 of the upperlimits specified.

The compounds prepared according to the invention may be administeredeither on their own or optionally in combination with other activesubstances for the treatment of migraine by intravenous, subcutaneous,intramuscular, intrarectal, intranasal route, by inhalation,transdermally or orally, while aerosol formulations are particularlysuitable for inhalation. The combinations may be administered eithersimultaneously or sequentially.

Categories of active substance which may be used in the combinationinclude e.g. angiotensin II receptor antagonists, α-agonists andα-antagonists, 5-HT_(1B/1D) agonists, AMPA antagonists, mild analgesics,antidepressants, antiemetics, anticonvulsants, antimuscarinics,βblockers, calcium antagonists, corticosteroids, ergot alkaloids,histamine-H1 receptor antagonists, neurokinine antagonists,neuroleptics, non-steroidal antiinflammatories, NO-synthase inhibitors,prokinetics, selective serotonin reuptake inhibitors or otheranti-migraine agents, which may be formulated together with one or moreinert conventional carriers and/or diluents, e.g. with corn starch,lactose, glucose, microcrystalline cellulose, magnesium stearate,polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof, into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions, solutions, metered dose aerosols or suppositories.

Thus other active substances which may be used for the combinationsmentioned above include for example the non-steroidal antiinflammatoriesaceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac,diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin,ketoprofen, leflunomide, lomoxicam, mefenamic acid, naproxen,phenylbutazone, piroxicam, sulphasalazine, zomepirac or thepharmaceutically acceptable salts thereof as well as meloxicam and otherselective COX2-inhibitors, such as for example rofecoxib and celecoxib.

It is also possible to use candesartan, eprosartan, irbesartan,losartan, olmesartan, tasosartan, telmisartan, valsartan, duloxetine,ergotamine, dihydroergotamine, metoclopramide, domperidone,diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin,timolol, isometheptene, pizotifen, botox, gabapentin, topiramate,riboflavin, montelukast, lisinopril, prochloroperazine, dexamethasone,flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol,nadolol, atenolol, clonidine, indoramin, carbamazepine, phenytoin,valproate, amitryptiline, lidocaine or diltiazem and other5-HT_(1B/1D)-agonists such as, for example, almotriptan, avitriptan,eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan andzolmitriptan and the physiologically acceptable salts thereof.

The dosage of these active substances is expediently ⅕ of the lowestrecommended dose to 1/1 of the normally recommended dose, i.e. forexample 20 to 100 mg of sumatriptan.

The invention further relates to the use of the compounds according tothe invention as valuable adjuvants for the production and purification(by affinity chromatography) of antibodies as well as in RIA and ELISAassays, after suitable radioactive labelling, for example by tritiationof suitable precursors, for example by catalytic hydrogenation withtritium or replacing halogen atoms with tritium, and as a diagnostic oranalytical adjuvant in neurotransmitter research.

1. A compound of the formula

wherein A denotes a group of formula

X denotes an oxygen atom, a methylene or NH group, R¹ denotes a group of formula

—NR²R³ denotes a group of formula

or a tautomer or salt thereof.
 2. A compound in accordance with claim 1, selected from the group consisting of those numbered successively from (1) to (2353) in the Table in the specification, or a tautomer or salt thereof.
 3. A compound in accordance with claim 1, selected from the group consisting of: (a) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4′]bipiperidinyl-1′-yl-2-oxo-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate, (b) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin -1-yl]-2-oxo-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate, (c) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4, 5-c]quinolin-3-yl)-piperidine-1-carboxylate, (d) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate, (e) 4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carboxylate (R)-1-4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl, (f) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carboxylate, (g) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carboxylate, (h) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4′]bipiperidinyl-1′-yl-2-oxo-ethyl 4-(5-oxo-3-phenyl4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carboxylate, and (i) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carboxylate, or a tautomer or salt thereof.
 4. A physiologically acceptable salt of a compound according to one of claim 1, 2 or
 3. 5. A pharmaceutical composition containing a compound according to claim 1, 2 or 3, or a physiologically acceptable salt thereof, together with one or more inert carriers and/or diluents.
 6. A method for treating migraine or cluster headaches which comprises administering to a host in need of such treatment a compound according to claim 1, 2 or 3, or a physiologically acceptable salt thereof.
 7. A method for treating non-insulin-dependent diabetes mellitus (NIDDM) which comprises administering to a host in need of such treatment a compound according to claim 1, 2 or 3, or a physiologically acceptable salt thereof. 